Diminished synaptic function and loss of synapses are characteristic early elements of the neuropathology of AD usually attributed to neuronal deposition of neurotoxic Aβ peptide oligomers in plaques and phosphorylated tau protein in tangles. The distribution and extent of brain synaptic pathology in postmortem brain tissues of patients with AD correlate generally with the severity of premortem cognitive losses. Initial analyses of plasma neuron-derived exosome (NDE) content of several synaptic proteins in patients having AD showed lower levels relative to those of matched control subjects, that were similar to decreases in postmortem AD brain tissues. In cross-sectional studies, AD patient plasma NDE levels of the presynaptic proteins synaptotagmin and synaptophysin, and of the postsynaptic proteins synaptopodin and neurogranin were significantly lower than for control subjects. AD patient plasma NDE levels of the synaptic membrane protein GAP43, however, were only marginally lower than for control subjects. Longitudinal analyses of cargoes in NDEs from plasmas of subjects who were cognitively normal, but would develop definite AD dementia subsequently, showed significantly lower levels of these same synaptic proteins than in plasma NDEs of matched control subjects. Progressive decline of plasma NDE levels of synaptotagmin, synaptopodin and GAP43, but not of synaptophysin or neurogranin, was seen in these AD subjects two to ten years later at the time of diagnosis of AD dementia.
The synaptic proteins investigated initially are widely distributed in central nervous system (CNS) synapses and share functional properties of binding to some other synaptic proteins to form complexes capable of regulating synaptic calcium concentration, and controlling synaptic vesicle fusion, recycling and readily releasable pool size. In relation to the present invention, it has now been determined that two classes of proteins that have essential synaptic maintenance functions restricted to localized excitatory circuits, rather than those of the widely-distributed cluster initially studied, also are present at lower levels in postmortem brain tissues of AD patients, as compared to matched control subjects, and their losses have been seen to contribute directly to the pathogenesis of AD.